Update on antiretroviral treatment

So here we are… a little more than two months into our “clinical trial”, N=2, of antiretroviral treatment for X+ cultures from VIP Dx. Anything that I mention about any more people than us came to me from email or hearsay, good sources though they may be. 
I started AZT alone and added raltegravir a week later. I experienced a significant reduction in malaise after a few weeks. At about six weeks, I had a surge of energy and reduction of many odious symptoms that I consider to be vasospastic in nature, as well as a reduction in air hunger which has been ever present for a long time. I tried to add tenofovir at eight weeks, probably because I felt that I had plateaued. Also that someone had to try it, and I don’t feel particularly afraid of the drugs after where I’ve been. I took tenofovir for five days. From the third day on I experienced escalating neurological symptoms, so discontinued it. At the same time I received a couple of reports of people who had started raltegravir alone and became suddenly worse.
My daughter started treatment a week after I did. She waited to see whether I was going to keel over right away:). I am not comfortable reporting about her except in the most general way. It is too much of an invasion of privacy. However, she also experienced a surge of energy at about six weeks into treatment, then an upsurge of symptoms I consider to be inflammatory and returned to about baseline. Since her inflammatory symptoms were continuing, she decided to stop raltegravir at the same time I did.
We both stopped raltegravir for five days and both experienced an almost immediate worsening of symptoms, in my case all associated with vasospasm, in her case receptor insensitivity (hypoglycemic episodes), both worse than baseline. So a rebound…
We both went back on raltegravir and those symptoms improved again very quickly, about a day. My daughter had four episodes in five days off raltegravir and has had one little one in almost two weeks back on. She started tenofovir five days ago and has so far had no problem with it. Her inflammatory symptoms persist, as do my neurological ones, but it’s not even close to where we’ve been before. I continue to experience much less malaise than before starting. My energy is more potential than kinetic at the moment:), but sitting here writing this, I don’t feel that sick.
My feeling is that if I were starting now, I would probably start with AZT and tenofovir, wait a while and then try to add raltegravir. Raltegravir may turn out to be not the right drug. But for the moment, it’s what we have. And nothing has ever dragged my illness around like raltegravir. I find that completely encouraging for the long haul. I would also like to make clear that the adverse experiences that we have had are not consistent with the very well known direct toxic effects of the drugs. I have heard a few reports of people who have tried AZT/raltegravir in combination and the response is mixed, but it doesn’t seem that anyone has lost much for trying it so far. And it’s not no response, which would actually be the worst response.
My best guess is that AZT alone is not a good enough inhibitor of reverse transcriptase in crucial tissue reservoirs. When raltegravir is added there is potential for it to be too potent. There may be a build-up of unintegrated viral DNA. When the drug was stopped it allowed viral integration and invasion of new cells. X uses XPR1 receptors, present on every cell in the body, to invade new cells. XPR1 binding damage may be involved with disease expression. My daughter’s most trackable symptom is hypoglycemia related to insulin insensitivity. Mine are vasospastic events in various organ systems. My guess is that they are ANS mediated. It may be due to affected enervation of distal blood vessels on the arterial side. Or it may be that there is a viral reservoir in smooth muscle or endothelial cells, vasospasm perhaps mediated by the direct effect of released inflammatory cytokines. Either fits with the episodic nature of the events.
I am being contacted by people who are considering testing for X or starting treatment. It is obviously a self-selected group. But there is one commonality. All are well along on their long, sad journeys and are completely willing to be part of the experiment, hoping that others may benefit, especially all the young people who haven’t had a chance at life yet. Maybe it’s fitting that this is how it is happening given the decades of neglect. We’ll figure it out for ourselves. Some of us simply don’t have the time to wait.

Thoughts about Chronic Lyme Disease

I have been asked many back channel questions about Lyme treatment…
I am reporting as a patient. Certainly, I have no medical advice for any individual. I am not in practice. I am not selling anything. I am speaking of my own experience in the hope of sparing a few people what I have been through. My perspective comes from two decades in conventional medicine, a decade in alternative medicine, fifteen years of my own illness, including six years as a Lyme patient much of it spent on antimicrobials for Bb and other TBD’s. My daughter and I were treated by four of the best LLMDs. I had a PICC line for 2 years. I tried it all. I also considered or tried every alternative treatment imaginable. The only things that ever helped me were bioidentical hormone replacement in physiologic doses, diet and neurofeedback. Possibly I can point to some good after effects of a lot of oxygen exposure. That’s it. Tried everything. Took everything.

My western blot is positive for IgG bands 31 and 34 from Igenex. I have had more than one positive FISH for Babesia microti. I have positive serology for Bartonella henselae and quintana. I have had a positive PCR for Mycoplasma fermentans. All four members of my family, including my somewhat ill but working husband and my clinically healthy son, have similar TBD tests. The only real difference I see in testing, my family and others, is that it is possible that people who respond to antibiotics are more likely to be IgM positive for Lyme specific bands on west blot. My daughter had acute Lyme (with an EM rash and systemic symptoms) that was adequately treated and she was healthy for three years after that. She became ill again in early adolescence without another known tick attachment though we lived in a highly endemic area. My husband had cardiac “Lyme” that did not respond to antibiotics; in fact he developed chronic IBS symptoms due to C. diff from too many antibiotics. He got better just by refusing antibiotics and eating well, but it took a very long time. He still has very significant signs and symptoms of illness, but works at a physically demanding job and is a cyclist. My son who has suspicious Bb tests, was seen by the most well-known Lyme pediatrician in the world who chose not to treat him. There were others in the LLMD community who might have treated him. I shudder to think…

During the eight years that we lived in New England we went from seeing only dog ticks to seeing deer ticks, including tiny nymphs, almost daily in season. The nymphs are so small that it is likely they would be missed, especially in the hair. It seems to me that being bitten in such a highly endemic area is probably the rule for anyone who goes outside at all, or who has pets that come inside. We moved from a town and house that we loved in order to escape ticks and I still think that was the right decision. We have lived in the southwest for six years and have seen one dog tick in that time. We have three dogs that do not wear insecticides and that go in and out of the house. I do think it is very important for anyone with a chronic fatiguing illness to practice extreme avoidance of ticks. One thing a little different about me in terms of my personal microbiome from the average CFS/Lyme patient is that I’ve had a tremendous amount of exposure to exotic animals over the years, especially psittacine birds and many types of reptiles, but haven’t ever found any direct connection between that and my illness. And I had lots and lots of blood exposure at work before the days of universal precautions. I now think my earliest sign of illness was at age 25 during internship.

I think the use of antibiotics in this patient population is sometimes necessary but very problematic. There are gut issues already, almost always worsened by the introduction of antibiotics. The way they are being used here is a witch hunt in my opinion. I think that the idea that the progressive neuroimmune disorder seen in the “post Lyme” group is due to cyst forms of Bb is erroneous. Cyst forms exist for many bacterial forms, just as viruses remain unactivated for a lifetime. The patients are sensitive. For many who have been ill for a long time throwing huge doses of antibiotics at it is like shooting at an insect, nasty bug that it may be, with a bazooka. Lots of collateral damage.

It is very difficult for a doctor to tell a patient that there is nothing he or she can do. Patients demand prescriptions. But overprescribing makes things worse. I think you can do what you can to modify the host environment and many will regain a better level of wellness. In my private practice I found that patients often benefited tremendously by helping them to stop many harmful medications. I believe that all drugs are poison. But that doesn’t mean you might not want to take some. It is always a trade off and for many, long term antibiotics have a poor risk benefit ratio. At best it seems that they may postpone the inevitable a bit, but at a great cost.

I DO believe that there is a place for the use of antibiotics in this patient group, though I don’t think that anyone really has a handle on it. My daughter still seems to require some antibiotic coverage, though I believe she is better off if her antibiotics are intermittent. I do better with no antibiotics. It is trial and error for each individual at this point. Unfortunately the error part can be very destructive. In fact, the downside may be as great or greater than the upside. Time will tell for each person. The sad thing is that without clinical trials, all of that experience is wasted for the group as a whole.

It is important to note that the very few doctors who care for both “Lyme” and “ME/CFS” patients are completely unable to distinguish between the conditions clinically. The difference is that the CFS doctors don’t use antibiotics. They are more guilty of the indiscriminate use of antivirals which doesn’t seem from the outside to be as harmful as endless courses and combinations of antibiotics.

My family alone covers the spectrum of disease, but I have a much larger group than that to draw from in forming my opinions. The fact that some people do better with antibiotics doesn’t mean that it is a good idea for everyone who has ever been bitten by a tick.  There are LLMDs who will treat on clinical grounds alone, with no supporting serological evidence. I would just like to point out that errors of commission are just as bad as or worse than errors of omission.

I was an ILADS member for six years. I quit recently because I no longer feel an affiliation with it as an organization. That they continue to put forth their “Guidelines” in light of new information is very disappointing, to be polite. I do not think that their ideas are standing up well to the test of time. They seem unable to incorporate new discovery into their thinking and are just continuing to defend their entrenched ideas and past actions. Very sad for patients. It is one thing to be harmed in ignorance, another for physicians to persist in doing what they’ve been doing, even though it doesn’t work, when new information is available. It will all come out in the wash, but many more people will be harmed in the meantime.

I believe that this idea that, even without a clear salutary response, if you only persist long enough with antibiotics you will eventually get well, is a complete myth. The passage of time is not supporting that hypothesis. And believe me, I bought into it, hook, line and big giant sinker, because my daughter responded to antibiotics, until she didn’t. I never did, but that didn’t keep LLMDs from prescribing more and more antibiotics for five years. I have now been off antibiotics for almost a year and I am much better than at any time I was on them. Of course I am penniless from treatment and lost productivity.

Taking a broad spectrum antibiotic knocks down flora in a broad spectrum way. The “herx” is an inflammatory reaction from the release of antigen, but it has little or nothing to do with Bb in my opinion. A Jarisch-Herxheimer reaction is a specific response to treating syphilis and it includes a rash. The “herx” that Lyme patients get is not that, but an indication that the body is not dealing with the die-off. If you knew you had active Bb, you might want to go through it for a little while, but months, years? There must be a proper way to use antibiotics in this patient group, but nobody has a clue at this point. Antibiotics are used all the time with HIV patients to good effect.

I did it. I know many others who have done it. It doesn’t work for most. Find me 10 patients who were sick for years, went on antibiotics, didn’t respond in a few months, kept going anyway and are now “well” years later. In general “chronic Lyme” patients do not get “well”. I presume there is a subset of patients that take antibiotics, get better and go away. But I suspect that anyone who is still searching for the right protocol is unlikely to get well with more antibiotics, in any dose or combination. I presume the people who get well have Bb and that’s it.  I know of a few people who have done well on long term (many years) orals and they all had a definite response to treatment. Also they were never were treated with IV’s. They deteriorate quickly if they take a break and have to go back on.

I do not believe that treatment failure is because of co-infections. Bartonella and Babesia are there, but they are cleared or remain dormant in a healthy person. They are opportunists in this patient population. That doesn’t mean that they might not need to be treated sometime. Bartonella henselae is found in endocarditis, but it responds to treatment. The idea that these patients are being treated for suspected Bartonella with nothing more than minimally elevated IgG titers is nuts in my opinion. I know people who have permanent damage form quinolones and aminoglycosides because of the Bartonella witch hunt. Something like 40% of healthy people have positive Bartonella serology. When I lived in the Berkshires I had a darkfield microscope. I didn’t use it diagnostically in my practice. It was a hobby. But I can tell you that Babesia genus is not hard to see. There is even a pathognomonic finding, the Maltese cross, that is very easy to see. I saw live Babesia in the blood of perfectly healthy people in the southern Berkshires (center of Bb epidemic in the US). I am certainly not a microbiologist, but I am old enough to know how to use a microscope.

My own paradigm has shifted. I think that XMRV will turn out to be the underlying cause of all of the neuroimmune illnesses that have become so prevalent over the last 25+ years. My own approach at the moment is to treat my X+ culture with antiretrovirals. But even if I am incorrect, or correct but the drugs don’t work, I think what I am saying about the indiscriminate use of antibiotics is still true. I would use the treatment of other bacterial infections as a guide. If you are on the right tract, expect a response. Even in the treatment of certain infectious diseases that require longer treatment, like TB, leprosy and acne:), the sensible physician expects to see a clear cause and effect for his treatment.

All of the Lyme patients that I know about who have been tested for XMRV are positive. The only negatives I know are less sick CFS patients, though one did well on antibiotics in the past, but is not taking any now or for some years. I think that most of the chronic Lyme population, chronic meaning didn’t respond to a reasonable course of antibiotics, will turn out to be XMRV positive.

If the causative agent is a retrovirus, the approach to treatment is completely different than that required to treat a bacterial infection. In my opinion, the many metabolic deficits and neuroimmune dysfunction seen in this patient group are  much better explained by a viral rather than bacterial etiology. There is a resistance to being labeled with CFS, for good reason, because it is a syndrome without a cure, rather than a disease like Lyme that may be treatable. But treating for the wrong thing will never bring about the desired results.

For me, knowing that the fundamental cause of my illness is a retrovirus changes alternative strategies also. I am at the beginning of the XMRV journey, so my ideas are not yet formulated. However, my private practice was involved with the after effects of brain injury, including Lyme and CFS. The patients I treated with chronic fatiguing illnesses had generally already failed years of antibiotics before they came to me or were intolerant of antibiotics, so I acknowledge a preselected patient population, but I was able to help patients to make progress nevertheless. In particular hormone replacement in physiologic doses can be very useful for both men and women. Also neurofeedback, possibly oxygen therapy and certain herbs may be useful for some people. I also think that there may be a place for cognitive enhancers and “anti-aging” drugs. Carefully discontinuing psychiatric medications in particular, with the support of other therapies, is often very helpful. I think that SSRIs are very problematic in this patient population. They do not address the cause of the depression that is so prevalent, which I believe to be inflammatory in nature. Neurofeedback is very stabilizing and therefore useful for the many neuropsychiatric instabilities seen. There may also be a place for heart rate variability training, a type of biofeedback, for some of the manifestations of dysautonomia. The fundamental premise of complementary and alternative medicine is to support the host environment or tip the balance in favor of wellness. In patients who are very ill and marginally stable, interventions often must be finessed. In my clinic, I saw my patients quite frequently for an hour at a time over a long period of time. That’s what it takes. But even in the most dire of circumstances it is possible to make gains, sometimes even miraculous ones, with very gentle therapies.

The neglect and abuse that the patients have endured and are enduring every day is a complete travesty. But it is not because an efficacious treatment is being withheld. It is interesting that in the CFS community my thoughts have been seen as hopeful, but in the Lyme community no, because of a myth. CFS patients are almost better off because they are not being told that they can be saved by something harmful that is being withheld from them. I am trying to give people new to this problem pause before they dive right in. Taking that first doxycycline was the worst thing I ever did to my body. Antibiotics are not harmless. Lyme treatment took me down completely.
If you feel that something that could make you better is being denied to you, it becomes less important to prove efficacy than to try it. But lots of people have and I believe that there is a great deal of harm being done to patients, some of whom don’t even have active borreliosis, just serology that indicates that the organism is there. Lots of organisms persist in the body without causing active disease at any particular moment. I am not saying that I have the answer to the antibiotic question. It should be possible to consider the question while under the care of a competent infectious disease doctor. But because of the politics of the situation, patients are denied that option. It is a horrible situation, but unfortunately, endless antibiotics will not fix it. When people are very invested in a treatment, it is almost impossible for them to sort out what is going on. That goes for doctors and patients. I wish I could say, find a smart ID doctor to work with. But we all know that there are almost no competent doctors interested in treating this disease. So as a patient group we are on our own. My best advice is to find a compassionate GP to work with. And always remember that sometimes it is better to do nothing until a clear course of action presents itself. Primum non nocere.

False hope never helped anyone. Personally, I am hopeful that we will soon have an approach to this illness that is based on more than hoping.

Speculation about drug reaction

I ended up stopping tenofovir after five days. The symptoms that I experienced when I added the tenofovir were more consistent with a flare of my disease than anything to do with the known toxicity profile of the drug. In addition I had repeated my TGF beta-1 (the only potential marker I’ve ever found of my disease) and C4a which was high normal at baseline. TGF beta-1 was still astronomically high and C4a shot way up, on AZT/raltegravir, even though I didn’t feel worse when the labs were drawn. Shortly after that draw, I started to feel and function much better, then plateaued until I started the tenofovir. Repeat TGF beta-1 and C4a from just prior to starting tenofovir are pending. By the way, I am having safety labs every two weeks (blood count and metabolic panel).

I am following eight X+ patients from a distance (and one long term CFS patient who has chosen to start treatment with a negative culture). It is a mixed bag so far, but the two people I know of that started raltegravir alone didn’t do well in very short order (days). AZT alone seems to bring about a very modest improvement with little problems over a month or so, which is when the three patients I was following who were on it alone added raltegravir. Very small numbers and completely uncontrolled, but it’s all there is for now.

I took tenofovir for five days, by which time I was quite a bit worse than before I started it. At that point, I decided to stop raltegravir as well. It turns out that tenofovir can raise the level of raltegravir though it doesn’t seem to be clinically significant in AIDS patients (Raltegravir drug interactions). It is possible that raltegravir is such a potent inhibitor of XMRV integrase that there is a build-up of unintegrated DNA in the cell cytoplasm. DNA in the cytoplasm could activate production of interferons and thus, a resultant inflammatory response.  That is how it felt to me. Treatment with interferon alpha (example is treatment of Hepatitis C) can be associated with a plethora of side effects, many of which are CFS-like symptoms. 

Below are links to a few papers on measurement and modeling of the decay characteristics of HIV with treatment. It is worth noting that there is a first-phase rapid decay and a much slower second-phase decay. Though the exact mechanism for the later is still unknown, it is likely related to the infection of long-lived cells. Second-phase decay in AIDS patients treated with HAART takes years.

Personally, I feel best about AZT right now of the three drugs available. It prevents replication at the most basic point in the virus’ life cycle. It is the broadest spectrum if you will. It has been around the longest. There is vast experience with it over many years of treatment. It may be that raltegravir requires reduction of viral load before adding. Or it may be that we are like the genetically susceptible infected mice for whom it isn’t the right drug (Raltegravir autoimmunity). We desperately need viral load measures and organized clinical trials. But until then, I’ll keep reporting… 

I have heard from people considering AZT alone, sometimes at below HIV doses. I would still prefer more than one drug. We can’t know anything about how readily this virus will become resistant to drugs. We don’t know anything about XMRV’s RT error rate. We don’t know anything about viral load in target tissues.

I stayed off both drugs, on AZT alone, for 5 days. I continued to get sicker until I was well below baseline. Last night it seemed clear to me that I had been better off on the AZT/raltegravir protocol, so I decided to go back on raltegravir. Amazingly, I feel much better today. The horribleness seems to be fading into the background again. I am reporting now because I don’t know how it is going to turn out. But it is an almost A-B-A experiment. However the experiment turns out, what has happened already greatly surprises me.

It would have been a fairy tale if the drugs had just worked. So much for logic! I actually didn’t expect it to be that easy. The good news is that if the drugs can move the illness, it is supportive of the hypothesis that XMRV is causative in the pathogenesis of the disease. It seems to me, that if altering the viral load, or altering the build-up of viral particles in the cytoplasm can shift the clinical picture in either direction in days or weeks, viral replication must not be so slow. It is a pretty stunning observation if you think about it. Must be a really good (successful) pathogen to be replicating so freely in relative equilibrium with the host over so many years. Doesn’t kill for a very long time. Clinical observation is that trying to alter things often doesn’t work out so well with CFS patients. Hence the observation that the patients are “sensitive”. Actually I think we are very tough.

Personal report

I have been reluctant to report anything publicly with respect to the effects of antiretrovirals. It is my belief that without the benefit of clinical trials to guide us, each person who chooses to go down this road at this time should decide on their own with the scientific information currently available. I didn’t want to influence that decision with a single positive report. But I’ve changed my mind about reporting, as, incredibly, my response to treatment is a significant fraction of the clinical information currently at hand for those trying to decide how to proceed.
I am Harvard/Einstein educated. My medical school training took place mostly in county hospitals in the Bronx. My father was a brilliant surgeon and I wanted to follow in his footsteps, but wanted a life too. Things weren’t too great for women in surgical training back then. So I became an emergency physician, before there was such a thing, and a surgical first assistant in a community hospital where I was the director of the ER.
From ’86-’96 I worked at Santa Clara Valley Medical Center in San Jose, CA. It is the Stanford affiliated county hospital, regional burn, spinal cord injury and neonatal intensive care units. During that time I became the assistant director of the ED and director of Urgent Care. Before becoming a mother, I flew a few shifts a month for Stanford LifeFlight. I was the queen of stress.
I never saw a doctor until I was 41, including two home births. I had my first neurological symptom (sensory) when my second baby was four months old and nursing. It came and went for four days. I thought I had MS, then it went away entirely and I forgot about it. In the year that followed, I experienced several recurring seemingly unrelated problems. In hindsight, they were all different manifestations of vascular instability and dysautonomia. About a year after my first overt symptom, I experienced a series of personal tragedies in quick succession. Shortly, thereafter, I developed symptoms that precluded working.
When I stabilized from the crash, I didn’t seek treatment. As a doctor, I intuitively knew that there was no help. I recovered enough with no treatment to have a private practice. In my practice, I treated the after effects of brain injury alternatively, predominantly with HBOT and neurofeedback, including patients with ASD, Lyme Disease and ME/CFS (not always identified as such). In ’03, my entire family was diagnosed with Lyme Disease. My daughter had had acute Lyme in ’00 that was successfully treated, but in ’03 became ill without another known tick bite. She was antibiotic responsive, leading us to six years of treatment by LLMD’s with disastrous results. I have been critically ill twice since then. Last summer, I fired my doctors and went off all treatment. I have been on an up-hill trajectory since then.
Even though I treated patients, I never identified with ME/CFS though I now meet all sets of diagnostic criteria. Until I was treated for Lyme, I didn’t consider myself fatigued. I was still very athletic. My “fatigue” consisted of an inability to tolerate sustained mental activity. I had symptoms of vascular instability related to working, and in my last two years of practice, I had to shorten my work day. Depression and brain fog are not part of my symptom complex (except medication induced). I have had a sleep disturbance since working 36 hours on/12 off for months at a time as an intern and I worked 24 hour shifts in the ER for years followed by many years of night shifts. I have had malaise most of the time since my first crash in ’96. I’m not interested in sharing my long list of symptoms. All CFS/Lyme patients have such a list. Vascular instability and a relapsing, remitting very slow degenerative neurological process define my illness, with almost autoimmunity.

When I first saw the Science paper a few days after it was published, it was an ah-ha experience for me. I knew very little about viruses and almost nothing about retroviruses. But what little I did know enabled a fusion of everything I’d learned as a doctor and a patient. So much so, that as I sent my daughter’s and my blood for culture, I thought, if it isn’t this one, there’s another one out there. Here was the fundamental cause of all the subtle and not so subtle things that had gone wrong with my entire family, including the opportunistic infections, the genetic piece, an explanation for vertical transmission and even the activation by stress that matched my direct experience (the virus has a glucocorticoid receptor element in it’s promotor region). I also saw X in my family of origin, members of whom have had aggressive prostate cancer, autistic spectrum disorder and Lyme Disease. So I had a lot of clues.

For me, understanding is everything. I finally know what I am fighting. I expected that it would be years before there was meaningful treatment. But when the Sakuma paper was published, even though only one drug was inhibitory, I became more hopeful for the near future. I have been sailing around in the fog without a navigator for so long, that the Singh paper seems like a having GPS to me.
I had a mild neurotoxic reaction to starting AZT, that has subsided incompletely (still have peripheral paresthesias increased from baseline). Cheap stuff. Easy to tolerate. About a week after starting Isentress, so during the third week of treatment, I experienced a noticeable reduction in malaise, always a prominent symptom for me. During the beginning of the sixth week, I experienced an increase in energy and ability to be semi-functional for several hours a day. Previously, I was essentially couchbound and going to town was a monumental effort. I can now run to town for a few errands and it’s not a big deal. Other symptoms are better as well. Neurologically, I think I am a little worse, but it is manageable.
I posted that I had started tenofovir a few days ago. The last day and a half have been very bad for me. Definitely toxic. I am reporting now because I believe that this is how it’s going to be. This is NOT going to be a bed of roses. I have been sick a very long time. I am a canary in the coal mine. We have no way of knowing what immune reconstitution might look like. There isn’t much science to follow, except for what has been learned from managing AIDS, a very different bug. It’s going to be a long time before the scientific community helps us. Even our own doctors seem to be slow on the uptake. I don’t know of a single clinical trial that is in the works. Testing even seems to be controversial in some circles.

I am an ER doctor by nature still. Triage. Impact the process where you can. Take care of the people circling the drain first. I am very far down the road so I am in that category. 

I am trying to decide whether to continue the third drug or not. I would not stop the other two right now for anything. Just having the malaise controlled is worth it for me. I am not particularly frightened that anything is going to happen that won’t reverse with stopping one or more drugs. Calculated risk. I know what happens if I don’t treat it.